With the rapid increase of the aging population, establishment of methods for treating dementia, such as Alzheimer-type dementia and cerebrovascular dementia, and ADHD is strongly demanded. Development of therapeutic agents for these diseases is studied using various approaches. Since these diseases are associated with a decreased cholinergic function in the brain, development of an acetylcholine precursor inhibitor or an acetylcholine esterase inhibitor was proposed as a promising direction, and these inhibitors are applied in clinical practice. Common examples of the acetylcholine esterase inhibitors include donepezil hydrochloride (1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine hydrochloride), rivastigmine (3-[1-(dimethylamino)ethyl]phenyl N-ethyl-N-methylcarbamate), metrifonate (dimethyl (2,2,2-trichloro-1-hydroxyethyl)phosphate), tacrine hydrochloride (1,2,3,4-tetrahydro-9-acridinamine), galanthamine hydrobromide, neostigmine, and physostigmine. Derivatives of these compounds are also under investigation (for example, see Patent Literature 1). For example, it has been mentioned that some physostigmine derivatives can suppress the production of β amyloid precursor protein (βAPP) upon administration (for example, see Patent Literature 2).
Butyrylcholinesterase is a serine hydroxylase that catalyzes hydrolysis of choline esters including acetylcholine and is extensively localized in the nervous system. Therefore, butyrylcholinesterase is thought to play an important role in the nervous system functions, in particular, cholinergic neurotransmission (for example, see Non Patent Literature 1). In fact, an invention has been disclosed that a highly selective butyrylcholinesterase inhibitor, such as cymserine, is used for the prevention or treatment of cognitive impairment associated with aging or Alzheimer's disease (for example, see Patent Literature 3). Some reports have shown that selective inhibition of a butyrylcholinesterase, such as (−)-N1-phenethylnorcymserine (PEC), increased the acetylcholine concentration in the brain, enhanced the learning ability, and decreased the amount of β amyloid peptide in animals with Alzheimer's disease in mice, rats, and the like (for example, see Non Patent Literature 2). Furthermore, both optical isomers of N1-norphenserine were synthesized, and an acetylcholine esterase inhibitory activity and a butyrylcholinesterase inhibitory activity of each optical isomer and a racemate consisting of these optical isomers at a ratio of 1:1 were measured. Both the optical isomers and the racemate all have been found to have both the inhibitory activities. Furthermore, effect on βAPP secretion in cultured human nerve cells was investigated. Both the optical isomers have been reported to have an effect of suppressing the βAPP secretion (for example, see Non Patent Literature 3). In addition, synthesis of a novel highly selective butyrylcholinesterase inhibitory compound derived from phenserine has also been attempted (for example, see Non Patent Literature 4).